Periodic hypothermia: a unusual syndrome in older patients

Periodic hypothermia is an under-recognised and therefore underdiagnosed condition that may present with neurological symptoms, particularly in patients with lesions affecting thermoregulatory pathways. This case highlights the diagnostic challenges in a patient with recurrent seizures and periodic hypothermia following a thalamic stroke.

Despite multiple interventions, the patient’s condition did not improve until the trial of clomipramine was initiated. Unfortunately, the patient passed away before the efficacy of the treatment could be assessed, underscoring the need for further research into the pathophysiology and management of periodic hypothermia.

What is periodic hypothermia?

Hypothermia is defined as a core body temperature of 35 degrees or lower and can result from various causes, including external environmental triggers, shock, infection and metabolic disorders (such as adrenal insufficiency and hypothyroidism). A lesser-known phenomenon, periodic hypothermia, is defined as intermittent episodes of reduced body temperature that are often associated with neurological symptoms.¹

This condition is most commonly seen in patients with lesions in the hypothalamus, thalamus, or corpus callosum and may present as part of the sequelae following stroke, trauma or other neurological insults, as well as due to congenital abnormalities, endocrine disorders or idiopathic causes.¹

Periodic hypothermia is an under-researched cause of neurological symptoms. As a result, it is under-recognised and often not considered as a potential cause for symptoms that are complex and not responding to usual management¹

Case study of periodic hypothermia

An 82-year-old female presented as an emergency to our hospital with slurred speech, right facial droop and right-sided weakness. Due to delayed presentation, she was not suitable for thrombolysis for acute ischaemic stroke.

The patient’s past medical history included total hip replacement, aortic stenosis, hyponatremia, and mild vascular dementia. She lived alone with a three-times daily care package and could mobilise short distances with a frame. An MRI head reported that there were numerous lacunar infarcts within the deep white matter of the left hemisphere. It confirmed left thalamic stroke with severe stenosis of the left carotid artery. Aspirin and atorvastatin were commenced for secondary stroke prevention.

Following the stroke, there were concerns throughout the admission due to recurrent seizure activity, often presenting as absence seizures associated with falls or incontinence. Treatment with lamotrigine was initiated, and she was discharged. However, she continued to have these episodes that led to numerous home visits and further hospital admissions.

After several months of ongoing symptoms, she was again admitted to our ward with a history of seizures. A repeat MRI head showed ‘an area of T2 hyperintensity in the left anterior pons, which might suggest chronic ischemic changes, though no acute infarcts were noted’.

Further investigations done during this admission showed septic screen negative, electrolytes, bone profile, serum B12 and folate and 9 AM cortisol were normal, TFTs showed a possible subclinical hypothyroidism (TSH 0.09, T4 14.9), and the autoimmune profile was negative. EEG showed ‘2Hz delta activity over anterior and central regions, spreading more posteriorly at times in both wakefulness and sleep, this could indicate disrupted brain activity’.

The stroke specialist advised that the condition could be a post-stroke seizure disorder, and levetiracetam 250mg once daily was added due to a lack of response to lamotrigine.

Specialist neurology advice was sought due to the persistent, frequent episodes not improving with the current anticonvulsant treatment. The neurologist also considered the diagnosis of post-stroke seizure disorder and titrated the lamotrigine tablets up to 50mg twice daily, with advice given to slowly uptitrate to 100mg BD if required.

The patient was discharged but was readmitted due to a fall with a head injury. CT scan showed right frontotemporal extra-axial haematoma measuring 5mm. In the emergency department, she had another seizure for which IV levetiracetam was given. Two days later, she had another witnessed seizure on the ward. Repeat CT head showed a stable subdural haematoma with no acute change.

She continued to have multiple short-lasting seizures in the hospital, and the family were becoming increasingly frustrated that the patient was not responding to treatment.

During this hospital stay, it was noticed that in between these seizure-like episodes, the patient was reasonably stable with normal observations. The chart interestingly showed intermittent temperature drops to 34-35 degrees. Nothing else remarkable was of note for this patient to account for this intermittent hypothermia. The EEG findings could have been consistent with the patient’s complex clinical presentation and possible thermoregulatory dysfunction.

A literature review was done for ‘periodic hypothermia’ and low-dose oral clomipramine was trialled. Unfortunately, the patient passed away a few weeks later due to unrelated causes before the success of the treatment could be determined. This further highlights the challenges in diagnosing and managing these patients.

Discussion

In normal physiology, there are several mechanisms by which the body responds to hypothermia. These include activation of the sympathetic nervous system to constrict surface blood vessels and reduce heat loss, the initiation of shivering to increase heat production, and adrenal release of catecholamines with hypothalamic release of thyroid-stimulating hormone to increase metabolic rate and generate additional heat.¹

The thalamus and the pre-optic nucleus of the hypothalamus tightly regulate these mechanisms. Neurotransmitters such as serotonin, melatonin, and catecholamines mediate the signals. Serotonin influences hypothalamic activity, and melatonin affects circadian rhythm and thermoregulation.

Disruptions to any of these pathways, whether due to structural brain abnormalities or neurotransmitter imbalances, can impair thermoregulation. Furthermore, damage to the corpus callosum, which facilitates interhemispheric communication, may hinder the integration of sensory information, including temperature signals, which in turn may impair thermoregulation.

There are many potential causes for these disruptions to thermoregulatory mechanisms. Firstly, any anatomical abnormality of the relevant areas of the brain, such as hypothalamic or pituitary tumours, may affect the hypothalamic-pituitary-adrenal (HPA) axis and release of thermoregulatory hormones. Endocrine factors can cause dysregulation of body temperature.

In addition to congenital conditions such as Shapiro syndrome,² acquired brain injuries can also play a significant role in disrupting thermoregulatory processes. Trauma leading to brain contusion and haemorrhage, or a stroke, may offset the body’s normal mechanisms if they are affecting the hypothalamus, thalamus or corpus callosum. This reinforces the importance of considering thermoregulatory dysfunction in stroke patients.

Our case presented is consistent with previous reports of thermoregulatory dysfunction following stroke, particularly in those with damage to the hypothalamus or thalamus. In our patient, the thalamic infarct is likely responsible for the impaired temperature regulation, contributing to the patient’s seizures and intermittent hypothermia.

Management of periodic hypothermia

There remains a significant gap in the literature regarding the pathophysiology and management of periodic hypothermia, but this is likely due to the lack of awareness and therefore recognition of the condition as a potential cause for neurological symptoms, especially in the older population.

Previous trials³ have found low-dose oral clomipramine to be effective, and its mechanism is believed to be due to its action on serotonin receptors. It is possible that acquired defects are more likely to be refractory to treatment. Drug therapy with clonidine, oxybutynin, carbamazepine, pizotifen, clomipramine and chlorpromazine has been successful in rare cases.³

Literature review of case reports

A previous case reported was one of an 82-year-old man who was found to have an enhancing mass in the hypothalamic region and subsequently developed periodic hypothermia, causing periods of lethargy and confusion.⁴

Shapiro syndrome⁵ is a rare condition characterised by hypothalamic dysfunction and agenesis of the corpus callosum that causes spontaneous periodic hypothermia, as well as hyperhidrosis. It is believed to be a congenital structural lesion and is a rare condition with less than 60 cases reported worldwide.³

Another case reported6 was one of a 53-year-old man who suffered a spontaneous subarachnoid haemorrhage and during rehabilitation, began to have periods of confusion and lethargy associated with a body temperature of 33 degrees. Further imaging showed ischemic changes in the corpus callosum. He was treated with 50mg oral clomipramine and had no further episodes.

Two cases were reported, one of a 72-year-old female with repeated episodes of spontaneous hypothermia, which resolved spontaneously, and another 72-year-old female with recurrent apathy and hypothermia episodes improved with levetiracetam.^7,8

Conclusion

The case in this report is consistent with a diagnosis of periodic hypothermia leading to absence seizures as a result of a thalamic infarct after a stroke. It highlights the importance of considering periodic hypothermia as a potential cause of neurological symptoms in patients with brain injuries, particularly those with hypothalamic, thalamic or corpus callosum damage. Clinicians should be aware of this rare but treatable condition, especially when managing patients with stroke or brain trauma.

Further research must be done into the condition to improve understanding of the mechanisms and establish more effective therapeutic strategies to reduce neurological complications and improve outcomes.

References

1. Blondin NA.Diagnosis and management of periodic hypothermia. Neurol Clin Prac.2014 Feb;4(1):26–33.
2. Ren L, Gang X, Yang S, Sun M, Wang G. A new perspective of hypothalamic disease: Shapiro’s syndrome. Front Neurol. 2022 Jul 29;13
3. Walker BR, Anderson JA, Edwards CR. Clonidine therapy for Shapiro’s syndrome. Q J Med1992;82(299):235–245
4. Arroyo HA, Di Blasi M, Grinszpan GJ. A syndrome of hyperhidrosis, hypothermia, and bradycardia, possibly due to central monoaminergic dysfunction. Neurology. 1990 Mar;40(3 Pt 1):556-7
5. Darku B, Kalra P, Prasad C, Yadav R. Episodic hyperhidrosis with corpus callosum agenesis: a rare case of Shapiro syndrome. Neurol India. 2011 2011 Jan-Feb;59(1):130-1.
6. Ferguson KM, Fyfe T, Montgomery J. A case of spontaneous hypothermia. Scott Med J. 1992;37:85–86.
7. Pierre Rossignon, Kenza El Alaoui, Alain. Spontaneous periodic hypothermia. Report of two cases. E j of case reports in IM. 2023: Vol 10 No 8
8. Hassene Attout, Sofia Amichi, Youcef Belkheir . Spontaneous periodic hypothermia in the elderly. A rare or underecognised syndrome. E J of case reports in IM.2020: Vol 7 No 12

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Dr Anna Grundy. Foundation doctor, Glangwili Hospital, Carmarthen, UK

Dr Abhaya Gupta, Consultant COTE, Glangwili Hospital, Carmarthen, UK

Conflict of interest: none declared